Imidazole derivatives or salts thereof and drugs containing the derivatives or the salts

ABSTRACT

The invention is directed to an imidazole derivative represented by formula (1):  
                 
 
     wherein each of R 1  and R 2  represents an aryl group, a heteroaryl group, etc.; each of A, X 1 , and X 2  represents N or CH; each of Y and Z represents O, S, etc.; each of R 3 , R 4 , and R 5  represents a hydrogen atom, an alkyl group, etc.; m is a number of 1 to 4; and n is a number of 0 to 4, or a salt thereof. The invention is also directed to a drug containing the derivative or the salt as an active ingredient. These compounds exert excellent effects of inhibiting production of NO and IL-6 and are useful for preventing or treating diseases induced by overproduction of NO and IL-6.

TECHNICAL FIELD

[0001] The present invention relates to a novel imidazole derivative ora salt thereof and to a drug containing the derivative or the salt as anactive ingredient.

BACKGROUND ART

[0002] Nitric oxide (NO) synthesized in living organisms by themediation of a nitric oxide synthase (NOS) is considered to be involvedin a variety of biological reaction steps.

[0003] Forchgott et al. disclose that endothelium-derived relaxingfactors (EDRFs) exert strong angiectatic effect and platelet aggregationinhibitory effect (1980). Palmer et al. disclose that the EDRFsessentially are in fact NO (1987). Further studies have revealed that NOis produced in vascular endothelial cells as well as in a variety oftissue cells in the whole body; e.g., the cerebellum, platelets,peripheral nerves, macrophages, polynuclear leucocytes, hepatocytes,Kupffer's cells, kidney mesangial cells, lung parenchyma cells, adrenalvascular smooth muscle, and fibroblasts. In addition to the previouslyidentified effect of relaxing vascular smooth muscle, NO has now beenelucidated to function as a neurotransmitter and exert various effectssuch as a cytotoxic effect on bacteria and oncocytes.

[0004] It has also been reported that when NO is overproduced andreleased in the body, a variety of cells and tissues are damaged becauseof high reactivity of NO stemming from its chemical instability and NO'seffect of relaxing vascular smooth muscle. Particularly, in recentyears, the relationship between inflammatory diseases and NO releasedfrom activated leucocytes has become of interest. Thus, a drug whichinhibits production of NO is envisaged to exert an anti-inflammatoryeffect.

[0005] Meanwhile, interleukin 6 (IL-6) is known to be produced fromcells such as monocytes, T cells, B cells, vascular endothelial cells,fibroblasts, and osteoblasts, and to exert a variety of physiologicaleffects including induction effects of differentiating B cells intoantibody-producing cells; for synthesizing acute phase protein fromhepatocytes; for differentiating cerebral nerve cells; for proliferatingand differentiating hematopoietic cells; and for differentiatingosteoclasts. In addition, the relationship between IL-6 and inflammationhas become of interest.

[0006] Chronic rheumatoid arthritis is a type of systemic chronicinflammatory disease in which the joints exhibit anomalous proliferationof connective tissue such as synovial tissue. As has been reported, anexcessive amount of IL-6 is present in the serum or synovial fluid ofchronic rheumatoid arthritis patients, and proliferation of synovialcells can be suppressed through administration of an antagonist forinhibiting IL-6 activity, such as an IL-6 antibody or an IL-6 receptor.

[0007] Among known physiological effects of IL-6, the aforementionedinduction effect of differentiating osteoblasts is considered to be afactor responsible for the onset of osteoporosis resulting from bonehyper-resorption of osteoblasts. Accordingly, a drug which inhibitsoverproduction of IL-6 is envisaged to be effective for chronicinflammatory diseases such as chronic rheumatoid arthritis and forosteoporosis.

[0008] Thus, an object of the present invention is to provide a novelcompound useful for preventing or treating a disease induced byoverproduction of NO or IL-6.

DISCLOSURE OF THE INVENTION

[0009] The present inventors have synthesized-a variety of compounds andcarried out extensive studies on pharmacological effects of thecompounds, and have found that imidazole derivatives or salts thereofrepresented by the below-mentioned formula (1) exert excellent effectsof inhibiting production of NO and IL-6 and are useful for preventing ortreating diseases induced by overproduction of NO and IL-6. Theinventors have also found that these derivatives and salts exert aneffect of inhibiting production of prostaglandin E₂ (PGE₂) but noulcer-inducing effect, which is an adverse side effect of non-steroidalanti-inflammatory drugs such as indomethacin. The present invention hasbeen accomplished on the basis of these findings.

[0010] Accordingly, the present invention provides an imidazolederivative represented by formula (1):

[0011] wherein

[0012] each of R¹ and R² represents a hydrogen atom, an alkyl group, ahalogen atom, an aryl group which may be substituted, or a heteroarylgroup which may be substituted;

[0013] each of A, X¹, and X² represents N or CH;

[0014] each of Y and Z represents O, S, SO, SO₂, CH₂, NH, or N—R⁶(wherein R⁶ represents an alkyl group, an aryl group which may besubstituted, or a heteroaryl group which may be substituted);

[0015] each of R³, R⁴, and R⁵ represents a hydrogen atom, an alkylgroup, an alkoxy group, a halogen atom, a halogenoalkyl group, a nitrogroup, an amino group, a hydroxyl group, a cyano group, an acyl group, acarboxyl group, a carbamoyl group, a substituted amide group, asulfonamide group, a substituted sulfonamide group, or a phenyl groupwhich may be substituted;

[0016] m is a number of 1 to 4; and

[0017] n is a number of 0 to 4,

[0018] or a salt thereof.

[0019] The present invention also provides a drug comprising, as anactive ingredient, the aforementioned imidazole derivative (1) or thesalt thereof.

[0020] The present invention also provides a drug composition comprisingthe aforementioned imidazole derivative (1) or the salt thereof and apharmaceutically acceptable carrier.

[0021] The present invention further provides use of the aforementionedimidazole derivative (1) or the salt thereof for producing a drug.

[0022] The present invention further provides a method for treating adisease induced by overproduction of NO or IL-6 characterized bycomprising administrating the aforementioned imidazole derivative (1) orthe salt thereof.

BRIEF DESCRIPTION OF THE DRAWING

[0023]FIG. 1 is a graph showing changes in inflammation score observedin Test Example 3.

BEST MODES FOR CARRYING OUT THE INVENTION

[0024] The compounds according to the present invention are representedby the aforementioned formula (1). Examples of the alkyl groupsrepresented by R¹, R², R³, R⁴, R⁵, or R⁶, include C1-C6, linear orbranched alkyl groups. Specific examples include methyl, ethyl,n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, pentyl, and hexyl.Of these, methyl and ethyl are particularly preferred.

[0025] Examples of the halogen atoms represented by R¹, R², R³, R⁴, orR⁵ include a fluorine atom, a chlorine atom, and a bromine atom. Ofthese, a chlorine atom is particularly preferred.

[0026] Examples of the alkoxy groups represented by R³, R⁴, or R⁵include C1-C6 linear or branched alkoxy groups. Specific examplesinclude methoxy, ethoxy, propoxy, isopropoxy, butoxy, pentyloxy, andhexyloxy. Of these, methoxy and ethoxy are particularly preferred.

[0027] Examples of the halogenoalkyl groups represented by R³, R⁴, or R⁵include C1-C6 linear or branched halogenoalkyl groups. Of these, thoseof C1-C3 are preferred, with a trifluoromethyl group being particularlypreferred.

[0028] Examples of the acyl groups represented by R³, R⁴, or R⁵ includealkanoyl groups such as C1-C6 alkanoyl groups. Specific examples includeformyl, acetyl, and propionyl.

[0029] Examples of the-aryl groups represented by R¹, R², R³, R⁴, R⁵, orR⁶ include C6-C14 aryl groups. Specific examples include phenyl,naphthyl, and anthranyl. Of these, phenyl and naphthyl are particularlypreferred. Examples of the heteroaryl groups include 5- or 6-memberedheteroaryl groups having one or two nitrogen, sulfur, or oxygen atoms.Specific examples include pyrrolyl, furyl, thienyl, imidazolyl, pyridyl,and pyrazinyl. Of these, thienyl, imidazolyl, pyridyl, and pyrazinyl areparticularly preferred.

[0030] Examples of the groups which can serve as a substituent for thearyl group or heteroaryl group represented by R¹ or R² include one tothree groups selected from among halogen atoms, a nitro group, aminogroups, alkyl groups, a hydroxy group, alkoxy groups, alkylthio groups,alkylsulfonyl groups, alkylenedioxy groups, and halogenoalkyl groups.Examples of the groups which can serve as a substituent for the arylgroup or heteroaryl group represented by R⁶ include alkyl groups, alkoxygroups, amino groups, and sulfonamide groups. Examples of the groupswhich can serve as a substituent for phenyl group represented by R³, R⁴,or R⁵ include alkyl groups, alkoxy groups, amino groups, and sulfonamidegroups. Examples of the groups which can serve as a substituent for theamide or sulfonamide group represented by R³, R⁴, or R⁵ include alkylgroups. Specifically, an alkanoylamino group is a preferred substitutedamide group, and an alkanesulfonamide group is a preferredsubstituted-sulfonamide group. Examples of the alkyl groups, alkoxygroups, halogen atoms, and halogenoalkyl groups which can serve as asubstituent for these aryl groups or heteroaryl groups include the samegroups as described in relation to the aforementioned R¹ to R⁶. Examplesof the alkylthio groups include C1-C6 linear or branched alkylthiogroups. Specific examples include methylthio and ethylthio. Examples ofthe alkylsulfonyl groups include C1-C6 linear or branched alkylsulfonylgroups. Specific examples include methylsulfonyl and ethylsulfonyl.Examples of the alkylenedioxy groups include C1 or C2 alkylenedioxygroups. Of these, methylenedioxy are is preferred.

[0031] Examples of the groups represented by R¹ or R² of formula (1)include a hydrogen atom; halogen atoms; C1-C6 alkyl groups; a phenyl ornaphthyl group which may be substituted by one to three substituentsselected from among a halogen atom, a nitro group, an amino group, aC1-C6 alkyl group, a hydroxyl group, a C1-C6 alkoxy group, a C1-C6alkylthio group, a C1-C6 alkylsulfonyl group, a C1-C2 alkylenedioxygroup, and a C1-C6 halogenoalkyl group; and a pyridyl, imidazolyl,pyrazinyl, or thienyl group which may be substituted by one to threesubstituents selected from among a halogen atom, a nitro group, an aminogroup, a C1-C6 alkyl group, a hydroxyl group, a C1-C6 alkoxy group, aC1-C6 alkoxy group, a C1-C6 alkylthio group, a C1-C6 alkylsulfonylgroup, a C1-C2 alkylenedioxy group, and a C1-C6 halogenoalkyl group.Examples of preferred groups represented by Y or Z include O, CH₂, NH,and N—R⁶ (R⁶=C1-C6 alkyl). Of these, O and CH₂ are particularlypreferred. Examples of preferred groups represented by R³, R⁴, or R⁵include a hydrogen atom, a halogen atom, a nitro group, an amino group,a C1-C6 alkyl group, and a C1-C6 alkoxy group. m preferably falls within1 to 3. n preferably falls within 0 to 2.

[0032] No particular limitation is imposed on the species of the salt ofthe imidazole derivative (1) of the present invention, and any of thesesalts may be used so long as the salts are pharmaceutically acceptable.Examples of the preferred salts include hydrogen halide salts such ashydrofluorides, hydrochlorides, hydrobromides, and hydroiodides;inorganic salts such as carbonates, nitrates, perchlorates, sulfates,and phosphates; lower-alkysulfonates such as methanesulfonates,ethanesulfonates, and trifluoromethanesulfonates; arylsulfonates such asbenzenesulfonates and p-toluenesulfonates; organic acid salts such asfumarates, maleates, succinates, citrates, tartrates, and oxalates;aminoacid salts such as glutamates and aspartates; and salts of analkali metal or alkaline earth metal such as sodium, potassium, orcalcium.

[0033] In addition, hydrates, a variety of pharmaceutically acceptablesolvates, crystal polymorphisms, etc. of the compounds represented byformula (1) also fall within the scope of the present invention.Stereoisomers attributed to asymmetric carbon are also included.

[0034] The imidazole derivatives (1) of the present invention may beproduced through the following production methods 1 to 5.

[0035] (R¹, R², X¹, X², A, Z, R³, R⁴, R⁵, and m represent the same asdefined above; Y¹ represents O, S, NH, or N—R⁶ (R⁶ represents the sameas defined above); n is a number of 1 to 4; W represents a leavinggroup).

[0036] Specifically, Compound (1-1) of the present invention representedby formula (1) (wherein Y is O, S, NH, or N—R⁶, and n is 1 to 4) may beproduced in the following manner. Compound (2) is reacted with Compound(3), to thereby form Compound (4) (Step 1). The aldehyde moiety of thethus-formed Compound (4) is reduced to the corresponding alcohol moietyby use of a reducing agent, to thereby form Compound (5) (Step 2). TheCompound (5) is reacted with a halogenating agent, followed by reactionwith an imidazole derivative (Step 3). Each step will next be describedin detail.

[0037] (Step 1)

[0038] Compound (2) is reacted with an aldehyde derivative (3) having aterminal leaving group in the presence of an appropriate base andsolvent, to thereby yield Compound (4).

[0039] Compound (2), serving as a starting material, is prepared throughany of known methods (e.g., disclosed in J. Am. Chem. Soc., 74, 1580(1952); J. Am. Chem. Soc., 107, 972 (1985); J. Org. Chem., 57, 550(1992); J. Org. Chem., 28, 3468 (1963); J. Org. Chem., 60, 1408 (1995);and Japanese Patent Application Laid-Open (kokai) No. 7-33752). Anycommercial reagent of Compound (3) may be used. Alternatively, Compound(3) may be produced through halogenation or sulfonylation of a terminalhydroxyl group of an aldehyde derivative synthesized through a knownmethod (e.g., disclosed in Journal of Heterocyclic Chemistry, 6, 243(1969) and Japanese Patent Application Laid-Open (kokai) No. 8-92228).Examples of the leaving group W include halogen atoms such as chlorine,bromine, and iodine; a methanesulfonyloxy group; a p-toluenesulfonyloxygroup; and a trifluoromethanesulfonyloxy group. Of these, amethanesulfonyloxy group is preferred.

[0040] Examples of the base employed in the reaction of Compound (2)with Compound (3) include sodium hydride, calcium hydride, potassiumt-butoxide, sodium hydroxide, potassium hydroxide, and potassiumcarbonate. No particular limitation is imposed on the type of solvent,and any solvent can be employed so long as the solvent does not affectthe reaction. Examples of the solvents include ethers such astetrahydrofuran and dioxane; hydrocarbons such as benzene and toluene;amides such as dimethylformamide, dimethylacetamide, andN-methyl-α-pyrrolidone; and sulfoxides such as dimethyl sulfoxide. Thereaction is carried out under ice-cooling conditions or refluxconditions. Preferably, the reaction is preformed in dimethylformamidein the presence of potassium carbonate at 70 to 100° C. for about 2 toabout 5 hours under stirring.

[0041] (Step 2)

[0042] Compound (4) is reduced by use of a reducing agent in thepresence of a solvent, to thereby yield the corresponding alcohol form(5).

[0043] Examples of the solvent employed in the above reduction includelower alcohols such as methanol and ethanol; and ethers such as ethylether and tetrahydrofuran. Examples of the reducing agents includesodium borohydride, lithium borohydride, and aluminum lithium hydride.Of these, sodium borohydride is preferred. The reduction is preferablycarried out under ice-cooling or at room temperature with stirring for0.5 to 2 hours.

[0044] (Step 3)

[0045] The thus-formed alcohol form (5) is treated with a halogenatingagent in the presence or absence of solvent, to thereby form thecorresponding halide, and the halide is reacted with an imidazolederivative, to thereby yield Compound (1-1) of the present invention.

[0046] Preferably, the alcohol form (5) is reacted with thionyl chloridein methylene chloride in the presence of a catalytic amount ofdimethylformamide, followed by removing the solvent through distillationunder reduced pressure. The residue was dissolved in dimethylformamide,and an imidazole derivative is added to the solution. The mixture isallowed to react at 90-100° C. for 1 to 2 hours.

[0047] (R¹, R², X¹, X², A, Z, R³, R⁴, R⁵, m, and n represent the same asdefined above).

[0048] (Step 4)

[0049] Compound (1-2) of the present invention represented by formula(1) (wherein Y is O) may be produced through Mitsunobu reaction (OrganicReaction 42, 335) of Compound (6) with an imidazole derivative (7)having a terminal hydroxyl group.

[0050] Specifically, triphenyl phosphine (1-3 eq.) and dialkyl (e.g.,dimethyl, diethyl, or dipropyl) azobiscarboxylate (1-3 eq.) are added toa solution of Compound (6) dissolved in a solvent (e.g., methylenechloride, tetrahydrofuran, benzene, toluene, ether, dioxane, ordimethylformamide, and the resultant mixture is allowed to react at −5°C. to reflux temperature for about 1 to about 24 hours, to thereby yieldCompound (1-2) of the present invention.

[0051] (R¹, R², A, Y, R³, R⁴, R⁵, m, and n represent the same as definedabove).

[0052] Compound (1-3) of the present invention represented by formula(1) (wherein each of X¹ and X² is N, and Z is O) may be produced in amanner similar to that employed in production method 2 (Step 4); i.e.,through Mitsunobu reaction of a pyrazine derivative (8) having aterminal hydroxyl group with an imidazole derivative (9) having aphenolic hydroxyl group.

[0053] The pyrazine derivative (8), serving as a starting material, canbe produced through any of known methods (e.g., methods disclosed inJapanese Patent Application Laid-Open (kokai) Nos. 7-33752 and7-126256).

[0054] (R¹, R², X¹, X², A, Z, R³, R⁴, R⁵, m, and n represent the same asdefined above, and p represents 1 or 2).

[0055] (Step 5)

[0056] Compound (1-5) of the present invention represented by formula(1) (wherein Y is SO or SO₂) may be produced by treating, with anoxidizing agent, Compound (1-4) of the present invention producedthrough the aforementioned Production methods 1 to 3.

[0057] Examples of the oxidizing agent include peracetic acid,perbenzoic acid, m-chloroperbenzoic acid, and permaleic acid. Of these,m-chloroperbenzoic acid is particularly preferred. By modifying theamount of the employed oxidizing agent, compounds of p=1 or p=2 can beproduced selectively.

[0058] (each of X³ and X⁴ represents a halogen atom; each of R⁷ and R⁸represents a hydrogen atom or a lower alkyl; R⁷ and R⁸ may be linked toform a ring; and A, X², R⁴, R⁵, Z, m, and n represent the same asdefined above).

[0059] Specifically, Compound (10) is reacted with an aldehydederivative (11), to thereby form Compound (12) (Step 6), followed byreaction with Compound (13), to thereby form Compound (14) (Step 7). TheCompound (14) is reduced (Step 2), and the reduced product is reactedwith a halogenating agent, followed by reaction with an imidazolederivative, to thereby yield Compound (1-6) of the present invention(Step 3).

[0060] (Step 6)

[0061] Compound (10) is reacted with an aldehyde derivative (11) in thepresence of an appropriate base and solvent, to thereby yield Compound(12). Examples of the base employed in the reaction include sodiumhydride, calcium hydride, potassium t-butoxide, sodium hydroxide,potassium hydroxide, and potassium carbonate. No particular limitationis imposed on the solvent employed in the reaction, and any solvent canbe employed so long as the solvent does not affect the reaction.Examples of the solvent employed in the reaction include ethers such astetrahydrofuran and dioxane; hydrocarbons such as benzene and toluene;amides such as dimethylformamide, dimethylacetamide, andN-methyl-α-pyrrolidone; sulfoxides such as dimethyl sulfoxide. Thereaction is performed under ice-cooling or reflux conditions.Preferably, the reaction is performed in tetrahydrofuran in the presenceof potassium t-butoxide at 70-100° C. for about 2 to about 5 hours understirring.

[0062] (Step 7)

[0063] Compound (12) is-reacted with Compound (13) in the presence of anappropriate catalyst, base, and solvent, to thereby yield Compound (14).

[0064] Examples of the catalyst employed in the reaction includetetrakis(triphenylphosphine)palladium, tris(dibenzylideneacetone)dipalladium-tri(t-butylphosphine), palladiumacetate-triphenylphosphine, anddichloro[1,1′-bis(diphenylphosphino)ferrocene]. Examples of the baseemployed in the reaction include sodium carbonate, sodium t-butoxide,sodium methoxide, cesium carbonate, sodium hydroxide, and potassiumphosphate. Examples of the solvent employed in the reaction includetoluene, benzene, xylene, tetrahydrofuran, and dioxane. The reaction isperformed under reflux conditions. Preferably, the reaction is performedin benzene in the presence of tetrakis(triphenylphosphine)palladium andan aqueous solution of sodium carbonate at 100° C. for about 2 to about20 hours under stirring.

[0065] The Compound (14) synthesized in Step 7 is subjected to theaforementioned Steps 2 and 3, to thereby produce Compound (1-6) of thepresent invention.

[0066] The thus-yielded Compounds (1) of the present invention can beisolated as crystal, liquid, or other forms through, in accordance withneeds, a routine separation-purification method such asrecrystallization, distillation, or chromatography.

[0067] The imidazole derivatives (1) of the present invention or saltsthereof exert effect of inhibiting production of NO and IL-6, andtherefore, are useful as drug for preventing or treating diseasesinduced by overproduction of NO or IL-6 (e.g., chronic inflammatorydiseases such as chronic rheumatoid arthritis and osteoarthritis; shock(e.g., septic shock); ulcerative colitis; ischemic brain disorders; andosteoporosis); NO production suppressors; IL-6 production suppressors;etc.

[0068] The drug of the present invention may be formed into a variety ofdrug preparations in accordance with the pharmaceutical action and thetarget, object, and form of administration. Specifically, the imidazolederivative (1) or a salt thereof in an amount for effective for servingas an active component is mixed with a known pharmaceutically acceptableadditive such as a vehicle, a binder, a disintegrant, a lubricant, asolution adjuvant, and a suspending agent, and the resultant mixture isformed into a preparation through a routine method.

[0069] Examples of the type of administration include peroraladministration by way of tablets, capsules, granules, powders, syrups,etc.; and non-peroral administration by way of injections, eye drops,suppositories, etc. The amount of the imidazole derivative (1) to beadministered varies in accordance with the condition, age, body weightof the patient, the way of administration, etc. Generally, the dailydose per adult is 0.1 to 1,000 mg and the drug is administeredpreferably once per day or several times per day in a divided manner.

[0070] The imidazole derivatives (1) of the present invention and saltsthereof can be administered to human, and serve as veterinary drugs forother mammals.

EXAMPLES

[0071] The present invention will next be described in more detail byway of examples, which should not be construed as limiting the inventionthereto.

Production Example 1 Synthesis of4-(2-[(5,6-diphenyl-2-pyrazinyl)oxy]ethoxy)benzaldehyde

[0072] To a mixture containing 5,6-diphenyl-2-pyrazinol (2.45 g),4-[2-(methanesulfonyloxy)ethoxy]benzaldehyde (2.44 g), and potassiumcarbonate (1.8 g), dimethylformamide (100 mL) was added. The resultantmixture was heated at 100° C. on an oil bath for two hours understirring, and the reaction mixture was poured into an ice-water mixture.The thus-formed organic matter was separated through extraction by useof ethyl acetate, followed by washing sequentially with water andsaturated saline. The washed product was dried over sodium sulfateanhydrate, and the residual solvent was removed through distillationunder reduced pressure. The thus-yielded residue was purified by meansof a silica gel column and crystallized from n-hexane, to thereby yield3.34 g of the title compound (yield 85.4%).

[0073]¹H-NMR (CDCl₃, δ): 4.46 (2H, t), 4.86 (2H, t), 6.94-7.52 (12H, m),7.71-7.88 (2H, m), 8.32 (1H, m), 9.90 (1H, m).

Production Example 2 Synthesis of(4-(2-[(5,6-diphenyl-2-pyrazinyl)oxy]ethoxy)phenyl)methanol

[0074] (4-(2-[(5,6-Diphenyl-2-pyrazinyl)oxy]ethoxy)benzaldehyde (2.90 g)was dissolved in ethanol (30 mL), and sodium borohydride (615 mg) wasadded to the resultant solution under ice cooling. The mixture wasstirred at room temperature for one hour. Subsequently, water was addedto the reaction mixture, and the thus-formed organic matter wasseparated through extraction by use of methylene chloride, followed bywashing sequentially by water and saturated saline. The washed productwas dried over sodium sulfate anhydrate, and the residual solvent wasremoved through distillation under reduced pressure. The thus-yieldedresidue was crystallized from n-hexane, to thereby yield 2.69 g of thetitle compound as colorless crystals (yield 92.3%).

[0075]¹H-NMR (CDCl₃,δ): 1.69 (1H, t), 4.37 (2H, t), 4.61 (2H, d), 4.82(2H, t), 6.83-7.04 (2H, m), 7.08-7.56 (12H, m), 8.31 (1H, s).

Production Example 3 Synthesis of4-{2-[(6-bromo-2-pyridinyl)oxy]ethoxy}benzaldehyde

[0076] To a 60% suspension of sodium hydride (0.22 g) in DMF (30 mL),4-(2-hydroxyethoxy)benzaldehyde (1.00 g) was added at 0° C., and thesuspension was stirred for 30 minutes. Subsequently, 2,6-dibromopyridine(2.14 g) and tetrabutylammonium iodide (0.022 g) were sequentially addedto the mixture at 0° C., and the resultant mixture was stirred at roomtemperature for two hours. After completion of reaction, the reactionmixture was poured into an ice-water mixture, and the thus-formedorganic matter was separated through extraction by use of ethyl acetate,followed by washing with water. The washed product was dried overmagnesium sulfate, and the residual solvent was removed throughdistillation under reduced pressure. The thus-yielded residue waspurified by means of a silica gel column, to thereby yield 1.50 g of thetitle compound as colorless crystals (yield 77.3%).

[0077]¹H-NMR (CDCl₃,δ): 4.40 (2H, t, J=4.9 Hz), 4.71 (2H, t, J=4.9 Hz),6.75 (1H, d, J=7.8 Hz), 7.07 (2H, d, J=8.8 Hz), 7.10 (1H, d, J=7.8 Hz),7.45 (1H, t, J=7.8 Hz), 7.85 (2H, d, J=8.8 Hz), 9.90 (1H, s).

Production Example 4 Synthesis of4-{2-[[6-(2,4-difluorophenyl)-2-pyridinyl]oxy]ethoxy}benzaldehyde

[0078] To a toluene (80 mL) solution containing4-{2-[(6-bromo-2-pyridinyl)oxy]ethoxy}benzaldehyde (1 g) andtetrakis(triphenylphosphine)palladium (0.18 g), a 2M aqueous solution (4mL) of sodium carbonate and a solution of2,4-difluorophenylbenzeneboronic acid (0.64 g) in ethanol (4 mL) wereadded. The resultant mixture was refluxed for four hours. Aftercompletion of reaction, the reaction mixture was poured into saturatedsaline, and the thus-obtained toluene layer of the resultant mixture wasseparated. The separated layer was dried over magnesium sulfate, and theresidual solvent was removed through distillation under reducedpressure. The thus-yielded residue was purified by means of a silica gelcolumn, to thereby yield 0.71 g of the title compound as colorlesscrystals (yield 64.5%).

[0079]¹H-NMR (CDCl₃,δ): 4.45 (2H, t, J=4.9 Hz), 4.81 (2H, t, J=4.9 Hz),6.77 (1H, d, J=7.8 Hz), 6.88-6.94 (1H, m), 6.97-7.01 (1H, m), 7.07 (2H,d, J=8.8 Hz), 7.42 (1H, dd, J=7.8,2.0 Hz), 7.67 (1H, t, J=7.8 Hz), 7.84(2H, d, J=8.8 Hz), 8.01-8.08 (1H, m), 9.89 (1H, s).

Example 1 Production of5-2-[4-(1H-imidazolylmethyl)phenoxy]ethoxy-2,3-diphenylpyrazine(Compound 1A of the Present Invention)

[0080] (4-(2-[(5,6-Diphenyl-2-pyrazinyl)oxy]ethoxy)phenyl)methanol(15.42 g) was dissolved in dichloromethane (360 mL). A catalytic amountof dimethylformamide and thionyl chloride (9.0 mL) were added to theabove solution, and the resultant mixture was stirred at roomtemperature for two hours. Then, the solvent and an excessive amount ofthionyl chloride were removed through distillation under reducedpressure. Imidazole (13.17 g) and dimethylformamide (80 mL) were addedto the residue, and the mixture was heated at 90° C. for two hours understirring. Subsequently, water was added to the reaction mixture, and thethus-formed organic matter was separated through extraction by use ofchloroform, followed by washing with water. The washed product was driedover sodium sulfate anhydrate, and the residual solvent was removedthrough distillation under reduced pressure. The thus-yielded residuewas purified by means of a silica gel column and crystallized fromn-propanol, to thereby yield 13.0 g of Compound (1A) of the presentinvention as colorless crystals (yield 80.0%).

Example 2

[0081] In a manner similar to that employed in Example 1, the followingcompounds of the present invention were produced: (1C), (1D), (1E),(1F), (1G), (1H), (1I), (1K), (1M), (1N), (1S), (1T), (1U), (1V), (1W),(1X), (1Z), (1AA), (1AB), (1AC), (1AD), (1AE), (1AF), (1AG), (1AH),(1AI), (1AK), (1AL), (1AM), (1AN), (1AP), (1AQ), (1AR), (1AS), (1AT),(1AU), (1AV), (1AW), (1AX), (1AY), (1AZ), (1BA), (1BB), (1BC), (1BD),(1BE), (1BF), (1BG), (1BH), (1BI), (1BJ), (1BK), (1BL), (1BM), (1BN),(1BO), (1BP), (1BQ), (1BR), (1BS), (1BT), (1BU), (1BV), (1BW), (1BX),(1BY), (1BZ), (1CA), (1CB), (1CC), (1CD), (1CE), (1CF), (1CG), (1CH),(1CI), and (1CJ).

Example 3 Production of5-(2-[4-(1H-imidazolylmethyl)phenoxy]ethoxy)-2,3-di(2-pyridyl)pyrazine(Compound 1B of the Present Invention)

[0082] 5,6-Di(2-pyridyl)-2-pyrazinol (1.21 g),2-[4-(1H-imidazolylmethyl)phenoxy]-1-ethanol (1.05 g), andtriphenylphosphine (1.27 g) were dispersed in tetrahydrofuran (30 mL). A40% solution (2.10 g) of diethyl azodicarboxylate in toluene was addeddropwise to the dispersion under ice cooling, and the resultant mixturewas allowed to react overnight, while the temperature of the mixture wasgradually elevated to room temperature. After completion of reaction,ethyl acetate was added to the reaction mixture, and the ethyl acetatelayer was washed with water. The washed product was dried over sodiumsulfate anhydrate, and the residual solvent was removed throughdistillation under reduced pressure. The thus-yielded residue waspurified by means of a silica gel column and recrystallized from ethylacetate, to thereby yield 960 mg of Compound (1B) of the presentinvention as pale yellow crystals (yield 44.0%).

Example 4

[0083] In a manner similar to that employed in Example 3, the followingcompounds of the present invention were produced: (1Q), (1Y), (1AE),(1AJ), and (1AO).

Example 5 Production of5-(3-[4-(1H-imidazolylmethyl)phenoxy]propyl)-2,3-diphenylpyrazine(Compound 1R of the Present Invention)

[0084] 3-(5,6-Diphenyl-2-pyrazinyl)-1-propanol (950 mg),4-(1H-imidazolylmethyl)phenol (570 mg), and triphenylphosphine (860 mg)were suspended in anhydrous tetrahydrofuran (30 mL). A 40% solution(1.56 g) of diethyl azodicarboxylate in toluene was added dropwise tothe resultant suspension under ice cooling, and the resultant mixturewas stirred at room temperature for one hour. Ethyl acetate was added tothe mixture, and the ethyl acetate layer was washed sequentially by a10% aqueous solution of sodium hydroxide, water, and saturated saline.The washed product was dried over sodium sulfate anhydrate, and theresidual solvent was removed through distillation under reducedpressure. The thus-yielded residue was purified by means of a silica gelcolumn and crystallized from ether, to thereby yield 500 mg of Compound(1R) of the present invention as colorless crystals (yield 34.0%).

Example 6

[0085] In a manner similar to that employed in Example 5, Compounds (1O)and (1P) of the present invention were produced.

Example 7 Production of5-(2-[4-(1H-imidazolylmethyl)phenoxy]ethyl)sulfinyl-2,3-diphenylpyrazine(Compound 1J of the Present Invention)

[0086]5-(2-[4-(1H-Imidazolylmethyl)phenoxy]ethyl)sulfanil-2,3-diphenylpyrazine(Compound 1I of the Present Invention) (464 mg) was dissolved inchloroform (20 mL), and m-chloroperbenzoic acid (260 mg) was added tothe solution. The resultant mixture was stirred at room temperature forthree hours. The reaction mixture was washed sequentially with anaqueous solution of saturated sodium bicarbonate and water. The washedproduct was dried over magnesium sulfate anhydrate, and the residualsolvent was removed through distillation under reduced pressure. Thethus-yielded residue was purified sequentially by means of an aluminacolumn and a silica gel column, to thereby yield 410 mg of Compound (1J)of the present invention as colorless crystals (yield 85.4%).

Example 8

[0087] The procedure of Example 7 was repeated except that the amount ofm-chloroperbenzoic acid was increased, to thereby yield Compound (1L) ofthe present invention. TABLE 1

Locant of R¹ R² X¹ X² A Y Z (CH₂)_(n) R³ R⁴ R⁵ m n m.p. (° C.) NMR (δppm) 1A

N N CH O O 4 H H H 2 1 132˜135 (CDCl₃): 4.37(2H, t, J=5.0 Hz), 4.81(2H,t, J=5.0 Hz), 5.05(2H, s), 6.87 (1H, s), 6.95(2H, d, J=9.0 Hz), 7.08(2H,d, J=9.0 Hz), 7.12(1H, s), 7.25˜7.46(10H, m), 7.52(1H, s), 8.32 (1H, s).1B

N N CH O O 4 H H H 2 1 118˜120 (CDCl₃): 4.37(2H, t, J=5.0 Hz), 4.83(2H,t, J=5.0 Hz), 5.05(2H, s), 6 88˜6.89(3H, m), 7.06˜7.10(3H, m),7.12˜7.24(2H, m), 7.53(1H, s), 7.61˜7.76(4H, m), 8.37˜8.39(3H, m). 1C

N N CH O O 4 H H H 2 1 90˜95 (HClsalt) (CDCl₃): 3.68(3H, s), 3.70(3H,s), 4.40(2H, t, J=4.9 Hz), 4.82(2H, t, J=4.9Hz), 5.37(2H, s),6.83˜7.19(9H, m), 7.21˜7.36(5H, m), 8.31(1H, s), 9.24(1H, s). 1D

N N CH O O 4 H H H 2 1 186˜189 (HClsalt) (CDCl₃): 4.39(2H, t, J=4.9 Hz),4.81(2H, t, J=4.9 Hz), 5.42(2H, s), 6.98˜7.06(7H, m), 7.33˜7.44(711, m),8.30(1H, s), 9.49(1H, s),; HClsalt. 1E

N N CH O O 4 H H H 2 1 150˜151 (CDCl₃): 4.34(2H, t, J=4.9 Hz), 4.75(2H,t, J=4.9 Hz), 5.05(2H, s), 6.67(1H, dd, J=1.0 Hz, 3.4 Hz), 6.84(1H, dd,J=3.4 Hz, 5.4 Hz) 6.88(1H, t, J=1.0 Hz), 6.94(2H, d, J=8.8 Hz), 7.07(1H,s), 7.09(2H, d, J=8.8 Hz), 7.29 (1H, dd, J=1.0 Hz, 5.4 Hz),7.40˜7.46(3H, m), 7.52˜7.55(3H, m), 8.25(1H, s). 1F

N N CH O O 4 H H H 2 1 212˜214 (HClsalt) (CDCl₃): 4.39(2H, t, J=4.9 Hz),4.81(2H, t, J=4.9 Hz), 5.36(2H, s), 7.00˜7.02(2H, m), 7.07(1H, s),7.26˜7.40(11H, m), 8.32 (1H, s), 9.15(1H,s),; HClsaIt. 1G

N N CH O O 4 H H H 2 1   189˜192.5 (HClsalt) (CDCl₃): 2.34(3H, s),2.36(3H, s), 4.38(2H, t, J=4.9 Hz), 4.81(2H, t, J=4.9 Hz), 5.37(2H, s),7.0˜7.12(7H, m), 7.26˜7.37(7H, m), 8.27(1H, s), 9.27(1H, s),; HClsalt.

[0088] TABLE 2 Locant of R¹ R² X¹ X² A Y Z (CH₂)_(n) R³ R⁴ R⁵ m n m.p.(° C.) NMR (δ ppm) 1H

N N CH O O 4 H H H 2 1 170˜172 (HClsalt) (CDCl₃): 2.30(3H, s), 2.31(3H,s), 4.38(2H, t, J=4.9 Hz), 4.82(2H, t, J=4.9 Hz), 5.45 (2H, s),6.98˜7.17(9H, m), 7.31˜7.36(5H, m), 8.29(1H, s) , 9.71(1H, brs)15.90(1H, br s),; HClsalt. 1I

N N CH S O 4 H H H 2 1 97˜99 (CDCl₃): 3.65(2H, t, J=6.8 z), 4.30(2H, t,J=6.8 Hz), 5.00(2H, s), 6.86˜6.90(3H, m), 6.9 4˜6.97(2H, m), 7.07(1H,s), 7.25˜7.33 (6H, m), 7.38˜7.44(4H,m), 7.50(1H, s), 8.50 (1H, s). 1J

N N CH SO O 4 H H H 2 1 56˜60 (CDCl₃): 3.54˜3.60(1H, m), 3.63˜3.69 (1H,m), 4.43˜4.48(1H, m), 4.55˜4.60(1H, m), 5.00(2H, s), 6.69˜6.72(2H, m),6.82 (1H, s), 7.01˜7.03 (2H, m), 7.06(1H, s), 7.29˜7.49(11H, m),9.14(1H, s). 1K

N N CH O O 4 H H H 2 1 128˜130 (CDCl₃): 4.37(2H, t, J=4.9 Hz), 4.80(2H,t, J=4.9 Hz), 5.05(2H, s), 6.89(1H, brs), 6.94 (2H, d, J=8.3 Hz),7.08(1H, brs), 7.11(2H, d, J=8.3 Hz), 7.28˜7.38(5H, m), 7.50·7.60 (5H,m), 8.36(1H, s). 1L

N N CH SO₂ O 4 H H H 2 1 135˜137 (CDCl₃): 3.95(2H, t, J=5.9 Hz),4.50(2H, t, J=5.9 Hz), 4.98(2H, s), 6.54˜6.56(2H, m), 6.80(1H, s),6.95˜6.97(2H, m), 7.05(1H, s), 7.26˜7.48(11H, m), 9.18(1H, s) 1M

N N CH O O 4 H H H 2 1 amorphous (CDCl₃): 4.38(2H, t, J=4.9 Hz),4.82(2H, t, J=4.9 Hz), 5.06(2H, s), 6.88(1H, s), 6.95 (2H, d, J=8.8 Hz),7.08(1H, s), 7.11(2H, d, J=8.8 Hz), 7.26˜7.55(10H, m), 8.33(1H, s). 1N

N N CH O O 4 H H H 3 1 91˜92 (CDCl₃): 2.29˜2.35(2H, dt, J=6.4 Hz), 4.17(2H, t, J=6.4 Hz), 4.64(2H, t, J=6.4 Hz), 5.03 (2H, s), 6.87˜6.90 (3H,m), 7.06˜7.10(3H, m), 7.25˜7.31(6H, m), 7.33˜7.38(2H, m), 7.43˜7.45(2H,m), 7.52(1H, s), 8.24 (1H, s). 1O

N N CH NH O 4 H H H 2 1   147˜148.5 (CDCl₃): 3.90˜3.94(2H, m), 4.20(2H,t, J=5.4 Hz), 5.05(2H, s), 5.10(1H, br), 6.88(1H, s), 6.91˜6.93(2H, m),7.08˜7.11(3H, m), 7.23˜7.35 (8H, m), 7.42˜7.44(2H, m), 7.52 (1H, s),8.00(1H, s).

[0089] TABLE 3 Locant of R¹ R² X¹ X² A Y Z (CH₂)_(n) R³ R⁴ R⁵ m n m.p.(° C.) NMR (δ ppm) 1P

N N CH N—CH₃ O 4 H H H 2 1 93˜96 (CDCl₃): 3.30(3H, s), 4.06(2H, t, J=5.9Hz), 4.24 (2H, t, J=5.9Hz), 5.02(2H, s), 6.86˜6.90(3H, m), 7.03˜7.07(3H, m), 7.22˜7.86(8H, m), 7.41˜7.44 (2H, m), 7.51(1H, s), 8.09(1H, s).1Q

N N CH O O 4 H H H 2 1 67˜71 (CDCl₃): 4.38(2H, t, J=4.9 Hz), 4.82(2H, t,J=4.9 Hz), 5.05 (2H, s), 6.88(1H, s), 6.94(2H, d, J=8.8 Hz), 7.04(1H,s), 7.12(2H, d, J=8.8 Hz), 7.48˜7.60(9H, m), 8.38(1H, s). 1R

N N CH CH₂ O 4 H H H 2 1 91˜92 (CDCl₃): 2.32˜2.38(2H, m), 3.11 (2H, t,J=7.3 Hz), 4.09(2H, t, J=6.4 Hz), 5.04(2H, s), 6.87·6.89 (3H, m),7.07˜7.09(3H, m), 7.26˜7.32(6H, m), 7.40˜7.44 (4H, m), 7.52(1H, s),8.49(1H, s). 1S

N N CH O CH₂ 4 H H H 1 1 202˜205 (CDCl₃): 3.14(2H, t, J=7.3 Hz),4.63(2H, t, J=7.3 Hz), 5.28(2H, s), 6.90(1H, s), 7.08˜7.12 (3H, m),7.25˜7.45(12H, m), 7.54(1H, s), 8.22(1H, s). 1T

N N CH O O 3 H H H 2 1 93˜94 (CDCl₃): 4.33(2H, t, J=4.8 Hz), 4.79(2H, t,J=4.8 Hz), 5.07(2H, s), 7.27˜7.54 (12H, m), 8.31(1H, s). 1U

N N CH O O 4 NH₂ H H 2 1 123˜126 (CDCl₃): 4.38(2H, t, J=4.9 Hz), 4.83(2H, t, J=4.9 Hz), 4.88(2H, brs), 5.05(2H, s), 6.88(1H, s),6.93˜6.96(2H, m), 7.08(1H, s), 7.10˜7.12(2H, m), 7.21˜7.26 (7H, m),7.33˜7.36(3H, m), 7.53(1H, s). 1V

N N CH O O 4 H H 2- CH₃ 2 1 144˜146 (CDCl₃): 2.34(3H, s), 4.36(2H, t,J=4.8 Hz), 4.80(2H, t, J=4.8 Hz), 4.97(2H, s), 6.81(1H, s),6.92˜7.01(5H, m), 7.26˜7.46(10H, m), 8.31(1H, s). 1W

N CH CH O O 4 H H H 2 1 Oil (CDCl₃): 4.35(2H, t, J=4.9 Hz), 4.78(2H, t,J=4.9 Hz), 5.03(2H, s), 6.83(1H, d, J=8.3 Hz), 6.87(1H, s), 6.95(2H, d,J=8.8 Hz), 7.07 (1H, s), 7.08(2H, d, J=8.8 Hz), 7.14(2H, d, J=7.8 Hz),7.18˜7.30 (6H, m), 7.37(2H, d, J=5.9 Hz), 7.52(1H, s), 7.63 (1H, d,J=8.3 Hz).

[0090] TABLE 4 Locant of R¹ R² X¹ X² A Y Z (CH₂)_(n) R³ R⁴ R⁵ m n m.p.(° C.) NMR (δ ppm) 1X

N N CH O O 4 H 2-OCH₃ H 2 1 108˜109 (CDCl₃): 3.80(3H, s), 4.44(2H, t,J=4.9 Hz), 4.83(2H, t, J=4.9 Hz), 5.05(2H, s). 6.65˜6.70 (2H, m),6.89(1H, s), 6.96(1H, d, J=8.3 Hz), 7.09(1H, s), 7.26˜7.39(8H, m),7.43˜7.45 (2H, m), 7.54(1H, s), 8.30(1H, s). 1Y

N N CH O O 4 H H H 2 0 135˜138 (CDCl₃): 4.42(2H, t, J=4.4 Hz), 4.85 (2H,t, J=4.4 Hz), 7.05˜7.07(2H, m), 7.19(1H, s), 7.21(1H, s), 7.28˜7.47(12H, m), 7.77(1H, s), 8.33(1H, s). 1Z

N CH CH O O 4 H H H 2 1   126˜127.5 (CDCl₃): 4.36(2H, t, J=4.9 Hz), 4.80(2H, t, J=4.9Hz,) 5.04(2H, s), 6.73˜6.82 (2H, m), 6.84(1H, d, J=8.3 Hz),6.88 (1H, t, J=1.5 Hz), 6.94˜6.97(2H, m), 7.04˜7.10(4H, m),7.22˜7.29(3H, m), 7.34˜7.36(2H, m), 7.52(1H, s), 7.58(1H, dd, J=8.3, 1.0Hz). 1AA

N CH CH O O 4 H H H 2 1   125˜127.5 (Fumarate) (CDCl₃): 4.34(2H, t,J=4.8 Hz), 4.67 (2H, t, J=4.8 Hz), 5.12(2H, s), 6.91˜6.99 (4H, m),7.12˜7.31(12H, m), 7.74 (1H, d, J=8.3 Hz), 7.80(1H, s).Fumarate 1AB

N N CH O CH₂ 4 H H H 2 1 147˜148 (CDCl₃): 2.12˜2.19 (2H, m), 2.83(2H, t,J=7.8 Hz), 4.45(2H, t, J=6.4 Hz), 5.08 (2H, s), 6.89(1H, s),7.07˜7.09(3H, m), 7.21˜7.44(12H, m), 7.54(1H, s), 8.24(1H, s). 1AC

N N CH O O 4 Cl H H 2 1 144.5˜146   (CDCl₃): 4.41(1H, t, J=4.9 Hz), 4.86(2H, t, J=4.9 Hz) 5.05(2H, s), 6.88(1H, s), 6.95˜6.97(2H, m), 7.07(1H,s), 7.09˜7.11 (2H, m), 7.26˜7.43(10H, m), 7.52(1H, s). 1AD

H N N CH O O 4 H H H 2 1 89˜91 (CDCl₃): 4.39 (2H, t, J=4.9 Hz), 4.83(2H,t, J=4.9 Hz), 5.05(2H, s), 6.88(1H, s), 6.93˜6.96 (2H, m), 7.07(1H, s),7.10˜7.13(2H, m), 7.46˜7.52(4H, m), 8.00˜8.03(2H, m), 8.22 (1H, s),8.63(1H, s).

[0091] TABLE 5 Locant of R¹ R² X¹ X² A Y Z (CH₂)_(n) R³ R⁴ R⁵ m n m.p.(° C.) NMR (δ ppm) 1AE

N N CH O O 4 H H H 2 0 149.5˜151   (CDCl₃): 4.42(2H, t, J=4.9 Hz), 4.83(2H, t, J=4.9 Hz), 6.98˜7.06(6H, m), 7.19(1H, s), 7.21(1H, s),7.31˜7.37(4H, m), 7.41˜7.45 (2H, m), 7.77(1H, s), 8.31 (1H, s). 1AF

N CH CH O O 4 H H H 2 1 133˜138 (3/2Fumarate) (DMSO-d₆): 4.35(2H, t,J=4.4 Hz), 4.69(2H, t, J=4.4 Hz), 5.11(2H, s), 6.62(3H, s), 6.91(1H, s),6.97˜7.00(3H, m), 7.13˜7.23(7H, m), 7.30˜7.33(1H, m), 7.68(1H, dt,J=7.8, 2.0 Hz), 7.78(1H, s), 7.79(1H, d, J=8.8 Hz), 8.46˜8.47(2H, m).Fumarate 1AG

N CH CH O O 4 H H H 2 1 93˜95 (Fumarate) (DMSO-d₆): 4.36(2H, t, J=4.9Hz), 4.70(2H, t, J=4.9 Hz), 5.11(2H, s), 6.62(2H, s), 6.90(1H, s),6.97˜6.99(3H, m), 7.15(1H, s), 7.21(2H, d, J=8.8 Hz), 7.27˜7.33(5H, m),7.53˜7.57(2H, m), 7.74(1H, s), 7.87(1H, d, J=8.3 Hz), 7.96(1H, brs),8.09˜8.12(1H, m).Fumarate 1AH

N CH CH O O 4 H H H 2 1 105˜113 (2 Fumarate) (DMSO-d₆): 4.35(2H, t,J=4.9 Hz), 4.67 (2H, t, J=4.9 Hz), 5.13(2H, s), 6.22 (1H, d, J=7.8 Hz),6.42(1H, t, J=2.0 Hz), 6.46(1H, dd, J=7.8, 2.0 Hz), 6.63(4H, s),6.86(1H, dd, J=8.3 Hz), 6.90(1H, t, J=7.8 Hz), 6.95 (1H, s), 6.99(2H, d,J=8.8 Hz), 7.19˜7.25 #(6H, m), 7.38˜7.40(2H, m), 7.46(1H, d, J=8.3 Hz),8.30(1H, brs). Fumarate 1AI

N CH CH O O 4 H H H 2 1 oil (CDCl₃): 4.34(2H, t, J=4.8 Hz),4.77(2H, t,J=4.8 Hz), 5.03(2H, s),6.67˜6.72(1H, m), 6.79(1H, d, J=8.3Hz), 6.87(1H,s), 6.90˜6.95 (2H, m), 7.02˜7.18(4H, m), 7.24˜7.45 (5H, m), 7.51(1H, s),7.66˜7.79(2H, m).

[0092] TABLE 6 Locant of R¹ R² X¹ X² A Y Z (CH₂)_(n) R³ R⁴ R⁵ m n m.p.(° C.) NMR (δ ppm) 1AJ

N N CH O O 4 H H H 3 0 162˜164 (1/2 Fumarate) (DMSO-d₆): 2.27(2H, q,J=6.4 Hz), 4.21(2H, t, J=6.4 Hz), 4.60(2H, t, J=6.3 Hz), 6.62 (1H, s),7.04˜7.08(3H, m), 7.29˜7.59 (13H, m), 8.09(1H, s), 8.35(1H, s),12.97(br).Fumarate 1AK

H N CH CH O O 4 H H H 2 1 118˜120 (CDCl₃): 4.37(2H, t, J=4.9 Hz), 4.82(2H, t, J=4.9 Hz), 5.03 (2H, s), 6.74 (1H, d, J=7.8 Hz), 6.95(2H, d,J=8.8 Hz), 7.07(1H, s), 7.10 (2H, d, J=8.8 Hz), 7.35˜7.47(4H, m),7.51(1H, t, J=7.8 Hz), 8.00˜8.03 (2H, m). 1AL H

N CH CH O O 4 H H H 2 1   94˜94.5 (CDCl₃): 4.34(2H, t, J=5.4 Hz),4.72(2H, t, J=5.4 Hz), 5.05(2H, s), 6.86˜6.99(6H, m), 7.07(1H, s),7.11(2H, d, J=8.8 Hz), 7.33˜7.74(1H, m), 8.26 (1H, brs). 1AM H

N CH CH O O 4 H H H 2 1 140˜141 (CDCl₃): 4.34(2H, t, J=5.3 Hz), 4.72(2H,t, J=4.8 Hz), 5.04(2H, s), 6.86˜6.96(4H, m), 7.06˜7.12(3H, m),7.35˜7.53(5H, m), 7.79˜7.82(1H, m), 8.01(1H, s), 8.36˜8.37(1H, m). 1AN H

N N CH O O 4 H H H 2 1   163˜164.5 (CDCl₃): 4.36 (2H, t, J=4.9 Hz),4.74(2H, t, J=4.9 Hz), 5.05(2H, s), 6.88(1H, s), 6.93˜6.96 (2H, m),7.07(1H, s), 7.11˜7.13(2H, m), 7.39˜7.50(3H, m), 7.52(1H, s),7.91˜7.93(2H, m), 8.36(1H, d, J=1.5 Hz), 8.51(1H, d, J=1.5 Hz). 1AO

H N N CH O O 4 H H H 3 0 88˜89 (CDCl₃): 2.34˜2.40(2H, m), 4.22(2H, t,J=5.9 Hz), 4.68(2H, t, J=5.9 Hz), 6.99˜7.01(2H, m), 7.18(1H, s),7.19(1H, s), 7.26˜7.30 (2H, m), 7.45˜7.51(3H, m), 7.75(1H, s),8.01˜8.03(2H, m), 8.16(1H, s), 8.60(1H, s).

[0093] TABLE 7 Locant of R¹ R² X¹ X² A Y Z (CH₂)_(n) R³ R⁴ R⁵ m n m.p.(° C.) NMR (δ ppm) 1AP

H N N CH O O 4 H H H 2 1 80˜81 (CDCl₃): 4.38(2H, t, J=4.9 Hz), 4.81(2H,t, J=4.9 Hz), 5.05 (2H, s), 6.88(1H, s), 6.93˜6.95(2H, m), 7.08(1H, s),7.11˜7.13(2H, m), 7.16˜7.20 (2H, m), 7.52(1H, s), 7.99˜8.02(2H, m),8.21(1H, s),8.58(1H, s). 1AQ H

N N CH O O 4 H H H 2 1   130˜131.5 (CDCl₃): 4.36(2H, t, J=4.9 Hz), 4.73(2H, t, J=4.9 Hz), 5.06(2H, s), 6.88(1H, s), 6.93˜6.95 (2H, m), 7.07(1H,s), 7.11˜7.18(4H, m), 7.52(1H, s), 7.88˜7.91(2H, m), 8.32(1H, d, J=1.5Hz), 8.46(1H, d, J=1.5 Hz). 1AR

N N CH O O 4 H H 4- NO₂ 2 1 61˜65 (DMSO-d₆): 4.40(2H, t, J=4.4 Hz), 4.74(2H, t, J=4.4 Hz), 5.22(2H, s), 7.00˜7.02 (2H, m), 7.28˜7.40(12H, m),7.94(1H, d, d=1.4 Hz), 8.38(1H, s), 8.40(1H, d, J=1.4 Hz). 1AS

N CH CH O O 4 H H H 2 1 94˜97 (CDCl₃): 4.35(2H, t, J=4.4 Hz), 4.78(2H,t, J=4.8 Hz), 5.04(2H, s), 6.74(1H, d, J=8.3 Hz), 6.86˜6.87(2H, m),6.94˜6.96(2H, m), 7.07˜7.16(6H, m), 7.27˜7.30(2H, m), 7.52(1H, s),7.58(1H, d, J=8.3 Hz). 1AT H

N N CH O O 4 H H H 2 1 154.5˜1.57.5 (CDCl₃): 4.36(2H, t, J=4.9 Hz),4.75(2H, t, J=4.9 Hz), 5.06(2H, s), 6.88(1H, s), 6.91˜7.03(4H, m), 7.07(1H, s), 7.11˜7.13(2H, m), 7.52(1H, s), 7.93˜7.99 (1H, m), 8.36(1H, d,J=1.5 Hz), 8.55˜8.56 (1H, m). 1AU

N N CH O O 4 H H 4- NH₂ 2 1 90˜93 (CDCl₃): 4.37(2H, t, J=4.9 Hz), 7.81(2H, t, J=4.9 Hz), 4.90 (2H, s), 6.16(1H, d, J=1.5 Hz), 6.92˜6.94(2H,m), 7.09˜7.11(2H, m), 7.16(1H, d, J=1.0 Hz), 7.26˜7.46 (10H, m),8.31(1H, s).

[0094] TABLE 8 Locant of R¹ R² X¹ X² A Y Z (CH₂)_(n) R³ R⁴ R⁵ m n m.p.(° C.) NMR (δ ppm) 1AV

N CH CH O O 4 H H H 2 1 oil (CDCl₃): 4.37(2H, t, J=4.8 Hz), 4.80(2H, t,J=4.8 Hz), 5.05(2H, s), 6.82(1H, d, J=8.3Hz), 6.88(1H, s), 6.94˜6.97(3H,m), 7.07˜7.21 (5H, m), 7.49˜7.58 (4H, m), 8.13(1H, s), 8.15˜8.20(1H, m).1AW

N CH CH O O 4 H H H 2 1 oil (CDCl₃): 3.60(2H, brs), 4.36(2H, t, J=4.8Hz), 4.79(2H, t, J=4.8 Hz), 5.04(2H, s), 6.45˜6.56 (3H, m), 6.63(1H, d,J=8.3 Hz), 6.77(1H, s), 6.84˜6.86(2H, m), 6.97˜7.06(5H, m),7.15˜7.19(2H, m), 7.41(1H, d, J=8.3 Hz), 7.46(1H, s). 1AX H

N CH CH O O 4 H H H 2 1   156˜157.5 (CDCl₃): 3.85(3H, s), 4.34(2H, t,J=4.8 Hz), 4.70(2H, t, J=4.8 Hz), 5.04(2H, s), 6.83˜7.12 (9H, m),7.43˜7.52(3H, m), 7.75˜7.76(1H, m), 8.31(1H, d, J=2.4 Hz). 1AY H

N N CH O O 4 H H H 2 1 125˜128 (CDCl₃): 4.37(2H, t, J=4.9 Hz), 4.76(2H,t, J=4.9 Hz), 5.06(2H, s), 6.88(1H, s), 6.93˜6.95(2H, m), 7.08(1H, s),7.12˜7.14(2H, m), 7.53(1H, s), 7.73(2H, d, J=8.3 Hz), 8.05(2H, d, J=8.3Hz), 8.37(1H, d, J=1.5 Hz), 8.55(1H, d, J=1.5 Hz). 1AZ H

N N CH O O 4 H H H 2 1 160˜161 (CDCl₃): 2.41 (3H, s), 4.35(2H, t, J=4.9Hz), 4.73(2H, t, J=4.9 Hz), 5.06(2H, s), 6.88 (1H, t, J=1.5 Hz),6.93˜6.96(2H, m), 7.07(1H, s), 7.11˜7.13(2H, m), 7.29(2H, d, J=8.3 Hz),7.53(1H, s), 7.81(2H, d, J=8.3 Hz), 8.33(1H, d, J=1.5 Hz), 8.48(1H, d,J=1.5 Hz). 1BA

H N N CH O O 4 H H H 2 1 127˜129 (CDCl₃): 4.37(2H, t, J=4.9 Hz),4.78(2H, t, J=4.9 Hz), 5.06(2H, s), 6.88(1H, s), 6.93˜7.04(4H, m),7.08(1H, s), 7.11˜7.13(2H, m), 7.52(1H, s), 8.00˜8.06(1H, m), 8.24(1H,s), 8.67(1H, d, J=2.0 Hz).

[0095] TABLE 9 Locant of R¹ R² X¹ X² A Y Z (CH₂)_(n) R³ R⁴ R⁵ m n m.p.(° C.) NMR (δ ppm) 1BB

H N N CH O O 4 H H H 2 1 119˜120 (CDCl₃): 2.43(3H, s), 4.38(2H, t,J=4.9Hz), 4.82 (2H, t, J=4.9 Hz), 5.05(2H, s), 6.88(1H, s), 6.93˜6.96(2H, m),7.07(1H, s), 7.11˜7.13(2H, m), 7.30(2H, d, J=8.3 Hz), 7.53 (1H, s), 7.91(2H, d, J=8.3 Hz), 8.18(1H, s), 8.60(1H, s). 1BC

H N N CH O O 4 H H H 2 1 125˜127 (CDCl₃): 3.88(3H, s), 4.38 (2H, t,J=4.9 Hz), 4.81 (2H, t, J=4.9 Hz), 5.05(2H, s), 6.93(1H, s), 6.94(2H, d,J=8.8 Hz), 7.01(2H, d, J=8.8 Hz), 7.07(1H, s), 7.12(2H, d, J=8.8 Hz),7.52(1H, s), 7.98(2H, d, J=8.8 Hz), 8.15 (1H, s), 8.57(1H, s). 1BD

H N N CH O O 4 H H H 2 1 85˜87 (CDCl₃3): 4.39(2H, t, J=4.9 Hz), 4.83(2H,t, J=4.9 Hz), 5.06(2H, s), 6.88 (1H, s), 6.94(2H, d, J=8.8 Hz), 7.08(1H,s), 7.12(2H, d, J=8.8 Hz), 7.52 (1H, s), 7.75(2H, d, J=8.3 Hz), 8.13(2H,d, J=8.3 Hz), 8.29(1H, s), 8.67(1H, s). 1BE

N N CH CH₂ CH₂ 4 H H H 2 1 96.5˜99  (3/2 Fumarate) (DMSO-d₆):1.64˜1.80(4H, m), 2.63(2H, t, J=7.3 Hz), 2.88(2H, t, J=7.8 Hz), 5.13(2H,s), 6.62(1.5H, s), 6.89(1H, s), 7.13˜7.19(5H, m), 7.27˜7.36(10H, m),7.72(1H, s), 8.56(1H, s). Fumarate 1BE

H N N CH O O 4 H H H 2 1 85˜87 (CDCl₃): 4.38(2H, t, J=4.9 Hz), 4.81(2H,t, J=4.9 Hz), 5.05(2H, s), 6.88˜6.95 (3H, m), 7.07˜7.13(3H, m),7.24˜7.31(1H, m), 7.52(1H, s), 7.72˜7.76(1H, m), 7.83˜7.89(1H, m), 8.23(1H, m), 8.57(1H, s). 1BG

H N N CH O O 4 H H H 2 1 112˜115 (CDCl₃): 4.38(2H, t, J=4.8 Hz),4.81(2H, t, J=4.8 Hz), 5.05(2H, s), 6.88˜6.95 (4H, m), 7.07˜7.13(3H, m),7.51˜7.55(3H, m), 8.27(1H, s), 8.59(1H, s).

[0096] TABLE 10 Locant of R¹ R² X¹ X² A Y Z (CH₂)_(n) R³ R⁴ R⁵ m n m.p.(° C.) NMR (δ ppm) 1BH

H N N CH O O 4 H H H 2 1 108˜111 (CDCl₃): 4.37(2H, t, J=4.8 Hz),4.78(2H, t, J=4.8 Hz), 5.05(2H, s), 6.88˜6.95 (3H, m), 7.07˜7.12(3H, m),7.42˜7.44(1H, m), 7.52(1H, s), 7.63˜7.65(1H, m), 7.95˜7.96(1H, m),8.15(1H, s), 8.50(1H, s). 1BI H

N CH CH O CH₂ 4 H H H 2 1 61˜63 (CDCl₃): 2.08˜2.15(2H, m), 2.81(2H, t,J=7.3 Hz), 4.34(2H, t, J=6.4 Hz), 5.08(2H, s), 6.80(1H, d, J=8.8 Hz),6.90˜6.98 (3H, m), 7.08˜7.09(3H, m), 7.22(2H, d, J=8.3 Hz),7.33˜7.39(1H, m), 7.54(1H, s), 7.71˜7.74(1H, m), 8.26(1H, s). 1BJ H

CH N CH O O 4 H H H 2 1   125˜128.5 (CDCl₃): 4.35˜4.37(2H, m), 4.41˜4.43(2H, m), 5.06(2H, s), 6.87˜7.01(5H, m), 7.08(1H, s), 7.13(2H, d, J=8.8Hz), 7.32(1H, dd, J=8.8, 2.9 Hz), 7.53 (1H, s), 7.71(1H, dd, J=8.8, 2.0Hz), 7.92˜7.98(1H, m), 8.45(1H, d, J=2.9 Hz). 1BK H

CH CH CH O O 4 H H H 2 1   172˜174.5 (CDCl₃): 4.35˜4.38(4H, m), 5.06(2H,s), 6.88(1H, s), 6.95(2H, d, J=8.3 Hz), 7.02 (2H, d, J=8.8 Hz), 7.08(1H,s), 7.12(2H, d, J=8.3 Hz), 7.31(1H, t, J=7.3 Hz), 7.42(2H, t, J=7.3 Hz),7.52˜7.57(5H, m). 1BL

N CH CH O O 4 H H H 2 1 amorphous (CDCl₃): 3.78(3H, s), 4.35(2H, t,J=4.8 Hz), 4.79 (2H, t, J=4.8 Hz), 5.04 (2H, s), 6.75˜6.87(6H, m),6.93˜6.96 (2H, m), 7.05˜7.11(4H, m), 7.29˜7.31(2H, m), 7.52(1H, s),7.54(1H, d, J=8.3 Hz). 1BM H

N CH CH O O 4 H H H 2 1   136˜137.5 (Fumarate) (DMSO-d₆): 4.36(2H, t,J=4.8 Hz), 4.67(2H, t, J=4.8 Hz), 5.13(2H, s), 6.92 (1H, s), 7.01(3H, t,J=8.3 Hz), 7.19(1H, s), 7.25(2H, d, J=8.7 Hz), 7.46(1H, d, J=6.8 Hz),7.52˜7.59(3H, m), 7.75˜7.80(2H, m), 7.85(1H, dd, J=8.7, 2.4 Hz),7.97˜8.03(2H, m), 8.27(1H, d, J=2.4 Hz). Famarate

[0097] TABLE 11 Locant of m. p. R¹ R² X¹ X² A Y Z (CH₂)_(n) R³ R⁴ R⁵ m n(° C.) NMR(δ ppm) 1BN

H N CH CH 0 0 4 H H H 2 1 64˜66 (CDCl₃): 4.35(2H, t, J=4.9Hz), 4.76(2H,t, J=4.9Hz), 5.05(2H, s), 6.77(1H, d, J=7.8Hz), 6.88˜7.00(5H, m),7.07(1H, s), 7.10(2H, d, J=8.8Hz), 7.41(1H, dd, J=7.8, 1.5Hz), 7.52(1H,s), 7.65(1H, t, J=7.8Hz), 8.02˜8.08(1H, m). 1BO

N CH CH 0 0 4 H H H 2 1 amor- phous (CDCl₃): 2.46(3H, s), 4.35(2H, t,J=4.8Hz), 4.78(2H, t, J=4.8Hz), 5.03(2H, s), 6.81(1H, d, J=8.3Hz),6.87(1H, s), 6.94˜6.96(2H, m), 7.04˜7.14(7H, m), 7.23-7.26(3H, m),7.37˜7.39(2H, m), 7.52(1H, s), 7.60(1H, d, J=8.3Hz). 1BP H

CH CH CH 0 0 4 H H H 2 1 111˜114 (CDCl₃): 4.32˜4.36(4H, m), 5.06(2H, s),6.88˜6.95(5H, m), 7.02(2H, d, J=8.8Hz), 7.08(1H, s), 7.12(2H, d,J=8.8Hz), 7.33˜7.39(1H, m), 7.44(2H, d, J=8.8Hz). 1BQ

H CH N CH 0 0 4 H H H 2 1 HCl salt 158˜162 (DMSO-d₆): 4.37˜4.39(2H, m),4.52˜4.54(2H, m), 5.39(2H, s), 7.03(2H, d, J=8.3Hz), 7.25(1H, dt, J=8.3,2.4Hz), 7.39˜7.45(3H, m), 7.66(1H, t, J=1.5Hz), 7.70˜7.77(3H, m),8.43(1H, t, J=1.5Hz), 8.45(1H, d, J=2.4Hz), 9.34(1H, s). Hclsalt 1BR H

N CH CH 0 0 4 H H H 2 1 94˜96 (CDCl₃): 4.34(2H, t, J=4.8Hz), 4.72(2H, t,J=4.8Hz), 5.05(2H, s), 6.85˜6.88(2H, m), 6.93˜6.96(2H, m), 7.07˜7.12(3H,m), 7.21˜7.33(3H, m), 7.52(1H, s), 7.73(1H, dd, J=8.5, 2.4Hz), 8.30(1H,d, J=2.4Hz). 1BS

CH CH CH 0 0 4 H H H 2 1 102˜103 (CDCl₃): 4.34˜4.41(4H, m), 5.05(2H, s),6.88˜7.37(19H, m), 7.52(1H, s).

[0098] TABLE 12 Locant of R¹ R² X¹ X² A Y Z (CH₂)_(n) R³ R⁴ R⁵ m n m. p.(° C.) NMR(δ ppm) 1BT H

N CH CH 0 0 4 H H H 2 1 113˜115 (CDCl₃): 4.34(2H, t, J=4.8Hz), 4.72(2H,t, J=4.8Hz), 5.05(2H, s), 6.77˜6.81(1H, m), 6.87˜6.89(2H, m),6.93˜6.95(2H, m), 7.02˜7.12(5H, m), 7.52(1H, s), 7.75(1H, dd, J=8.7,2.4Hz), 8.34(1H, d, J=2.4Hz). 1BU H

N CH CH 0 0 4 H H H 2 1 121˜124 (CDCl₃): 4.35(2H, t, J=4.8Hz), 4.73(2H,t, J=4.8Hz), 5.05(2H, s), 6.88˜6.95(4H, m), 7.07(1H, s), 7.10˜7.12(2H,m), 7.52(1H, s), 7.67(4H, dd, J=29, 8.7Hz), 7.82(1H, dd, J=8.7, 2.4Hz),8.39(1H, d, J=2.4Hz). 1BV H

CH CH CH 0 0 4 H H H 2 1 141˜143 (CDCl₃): 4.33˜4.39(4H, m), 5.06(2H, s),6.89(1H, s), 6.95(2H, d, J=8.3Hz), 7.06(2H, d, J=8.8Hz), 7.08(1H, s),7.13(2H, d, J=8.8Hz), 7.35(1H, dd, J=7.8, 4.9Hz), 7.53(2H, d, J=8.3Hz),7.54(1H, s), 7.84(1H, dt, J=7.8, 2.0Hz), 8.56(1H, dd, J=4.9, 2.0Hz),8.82(1H, d, J=2.0Hz). 1BW H

CH CH CH 0 0 4 H H H 2 1 139˜140 (CDCl₃): 4.31(4H, s), 5.05(4H, s),6.88(2H, s), 6.92(4H, d, J=8.8Hz), 7.07(2H, s), 7.11(4H, d, J=8.8Hz),7.52(2H, s). 1BX CH₃ H N CH CH 0 0 4 H H H 2 1 122˜124 (CDCl₃): 2.43(3H,s), 4.31(2H, t, J=4.8Hz), 4.66(2H, t, J=4.8Hz), 5.04(2H, s), 6.57(1H, d,J=7.8Hz), 6.72(1H, d, J=7.3Hz), 6.87(1H, s), 6.93˜6.95(2H, m), 7.06(1H,s), 7.09˜7.11(2H, m), 7.45(1H, t, J=7.3Hz), 7.51(1H, s). 1BY H

CH CH CH 0 0 4 H H H 2 1 118˜121 (CDCl₃): 4.35(4H, s), 5.06(2H, s),6.89(1H, s), 6.94(2H, d, J=8.8Hz), 7.04(2H, d, J=8.8Hz), 7.08(1H, s),7.13(2H, d, J=8.8Hz), 7.19(1H, s), 7.21(1H, s), 7.32(2H, d, J=8.8Hz),7.53(1H, s), 7.77(1H, s).

[0099] TABLE 13 Locant of m. p. R¹ R² X¹ X² A Y Z (CH₂)_(n) R³ R⁴ R⁵ m n(° C.) NMR(δ ppm) 1BZ H

N CH CH 0 0 4 H H H 2 1 118˜120 (CDCl₃): 4.35(2H, t, J=4.8Hz), 4.73(2H,t, J=4.8Hz), 5.05(2H, s), 6.88˜6.96(4H, m), 7.07˜7.13(3H, m),7.36˜7.40(1H, m), 7.52(1H, s), 7.79˜7.84(2H, m), 8.37(1H, d, J=1.9Hz),8.61(1H, dd, J=4.8, 1.4Hz), 8.80(1H, d, J=1.9Hz). 1CA H

CH CH CH 0 0 4 H H H 2 1 144˜146 (CDCl₃): 4.34˜4.41(4H, m), 5.09(2H, s),6.89(1H, s), 6.94(2H, d, J=8.8Hz), 7.08(1H, s), 7.09(2H, d, J=8.8Hz),7.13(2H, d, J=8.8Hz), 7.53(1H, s), 7.99(2H, d, J=8.8Hz), 8.45(1H, d,J=2.4Hz), 8.59(1H, dd, J=2.4, 1.5Hz), 8.99(1H, d, J=1.5Hz). 1CB H

N CH CH NCH₃ 0 4 H H H 2 1 96˜97 (CDCl₃): 4.02(2H, t, J=5.3Hz), 4.20(2H,t, J=5.3Hz), 5.02(2H, s), 6.59(2H, d, J=8.7Hz), 6.86˜6.94(5H, m),7.05˜7.09(3H, m), 7.32˜7.35(1H, m), 7.50(1H, s), 7.63(1H, dt, J=9.0,1.9Hz), 8.29(1H, s). 1CC H

N CH CH 0 0 4 H H H 2 1 139˜141 (CDCl₃): 4.34(2H, t, J=4.8Hz), 4.70(2H,t, J=4.8Hz), 5.04(2H, s), 6.00(2H, s), 6.82˜6.98(7H, m), 7.06˜7.12(3H,m), 7.52(1H, s), 7.72(1H, dd, J=8.7, 2.4Hz), 8.28(1H, d, J=1.9Hz). 1CD H

N CH CH 0 0 4 H H H 2 1 144˜146 (CDCl₃): 4.34˜4.36(2H, m), 4.63˜4.74(2H,m), 5.05(2H, s), 6.88˜6.95(4H, m), 7.07˜7.12(3H, m), 7.45˜7.52(3H, m),7.86(1H, d, J=6.3Hz), 8.45(1H, s), 8.66(2H, d, J=4.8Hz). 1CE H

N CH CH 0 0 4 H H H 2 1 200˜202 (DMSO-d₆): 4.31(2H, t, J=4.8Hz),4.60(2H, t, J=4.8Hz), 5.10(2H, s), 6.83˜6.88(4H, m), 6.95˜6.97(2H, m),7.12(1H, s), 7.21(2H, d, J=8.3Hz), 7.44˜7.46(2H, m), 7.69(1H, s),7.90(1H, dd, J=8.3, 2.48Hz), 8.36(1H, d, J=2.9Hz), 9.48(1H, s).

[0100] TABLE 14 Locant of m. p. R¹ R² X¹ X² A Y Z (CH₂)_(n) R³ R⁴ R⁵ m n(° C.) NMR(δ ppm) 1CF H

N CH CH 0 0 4 H H H 2 1 184˜186 (CDCl₃): 3.75(2H, brs), 4.38(2H, t,J=4.8Hz), 4.70(2H, t, J=4.8Hz), 5.04(2H, s), 6.75˜6.77(2H, m), 6.82(1H,d, J=8.7Hz), 6.87(1H, s), 6.92˜6.95(2H, m), 7.06˜7.12(3H, m),7.31˜7.33(2H, m), 7.52(1H, s), 7.74(1H, dd, J=8.5, 2.4Hz), 8.29(1H, d,J=2.4Hz). 1CG H

N CH CH 0 0 4 H H H 2 1 163˜166 (CDCl₃): 3.09(3H, s), 4.35(2H, t,J=4.8Hz), 4.74(2H, t, J=4.8Hz), 5.05(2H, s), 6.88˜6.95(4H, m),7.07˜7.13(3H, m), 7.52(1H, s), 7.70˜7.72(2H, m), 7.84(1H, dd, J=8.5,2.4Hz), 8.01(2H, d, J=8.3Hz), 8.41(1H, d, J=2.4Hz). 1CH F

CH CH CH 0 0 4 H H H 2 1 110˜112 (CDCl₃): 4.35˜4.37(4H, m), 5.06(2H, s),6.78˜6.95(5H, m), 7.07˜7.14(3H, m), 7.33˜7.38(2H, m), 7.52(1H, s),7.83(1H, dd, J=7.8, 1.9Hz), 8.57(1H, dd, J=4.8, 1.4Hz), 8.75(1H, s). 1CI

N N N 0 0 4 H H H 2 1 amor- phous (CDCl₃): 4.36(2H, t, J=4.4Hz),4.78(2H, t, J=4.4Hz), 4.80(2H, s), 6.53(1H, d, J=9.3Hz), 6.81(1H, s),7.09˜7.12(2H, m), 7.19(1H, brs), 7.28˜7.32(6H, m), 7.37˜7.42(4H, m),7.51(1H, s), 8.21(1H, s). 1CJ H

N CH N 0 0 4 H H H 2 1 63˜66 (3/2 Fuma- rate) (DMSO-d₆): 4.26(2H, d,J=4.9Hz), 4.59(2H, d, J=4.9Hz), 4.92(2H, s), 6.39(1H, d, J=9.3Hz),6.63(3H, s), 6.87(1H, d, J=8.3Hz), 6.90(1H, s), 7.13(1H, s),7.18˜7.21(1H, m), 7.33˜7.41(2H, m), 7.56˜7.62(1H, m), 7.73˜7.75(2H, m),7.87˜7.89(1H, m), 8.26(1H, s).

Test Example 1 Effect of Inhibiting Production of NO and IL-6

[0101] Growth of RAW 264.7 cells (mouse macrophage strains) wasmaintained in an RPMI 1640 medium containing 10% fetal bovine serum(FBS) and an antibiotic (10% FBS/RPMI) under culture conditions of 5%CO₂ at 37° C. Upon testing, RAW 264.7 cells were washed with coldDulbecco's phosphate buffered saline and subsequently removed from theplastic culture bottle by use of EDTA/trypsin. The thus-removed cellswere centrifuged-and washed, followed by dilution with 10% FBS/RPMI to4×10⁵/mL. The cell suspension (0.5 mL) was added to each well of a24-well-plate, and cultured under 5% CO₂, at 37° C. for 16 hours. Thepercent survival of the cells, as determined through the trypan blue dyeexclusion test, was found to be 95% or higher. The live cells werewashed once with 1% FBS/RPMI. Each test compound was diluted with thesame medium, to thereby adjust the concentration to a predeterminedlevel, and the liquid containing the test compound was added to thewashed cells. Two hours after addition, E.-coli-originatinglipo-polysaccharide (LPS 026:B6, product of SIGMA) whose concentrationhad been adjusted to a predetermined level with the medium was added tothe cells so as to adjust the final concentration to 25 ng/mL, wherebythe cells were stimulated for four hours. After completion ofstimulation, the culture suspension containing the test compound and LPSwas removed, and the cells were washed twice with the medium. The samemedium was added to each well (0.5 mL/well), and culture was furtherperformed for 17 hours. The resultant culture supernatant was stored at−20° C. until analysis of the supernatant. In each case, the test wasrepeated three times. NO contained in the culture supernatant wasquantitated for its stable form (NO₂ ⁻) by use of a Griess reagent kit(product of Wako Pure Chemical Industries Ltd.). IL-6 was quantitated byuse of an ELISA kit (product of Amersham) in accordance with the manualthereof. Percent inhibition of production of NO and IL-6 caused by thetest compound was calculated in accordance with the following equation:

Percent inhibition (%)=[(control−production in the presence of testcompound)/(control)]×100;

[0102] wherein the amount of produced NO or IL-6 in the absence of thetest compound was postulated to be 100%. The results are shown in Tables15 to 17. TABLE 15 NO production Compounds inhibitory of the effectinvention Percent (2 μg/mL) inhibition (%) 1A 86.0 1C 83.5 1H 83.5 1I62.8 1K 61.2 1M 82.6

[0103] TABLE 16 Compounds NO production of the inhibitory inventioneffect (0.02 Percent μg/mL) inhibition (%) 1Z 68.5 1AA 76.0 1AL 96.1 1AX60.4 1AY 93.9 1BJ 51.3 1BL 49.6 1BO 54.2 1BP 57.3 1BR 91.6 1BT 59.7 1BU98.0

[0104] TABLE 17 Compounds IL-6 production ofthe inhibitory effectinvention Percent (2 μg/mL) inhibition (%) 1A 54.6 1C 49.7 1H 65.2 1T77.9 1K 58.2 1M 51.7

[0105] The results shown in these Tables indicate that the compounds ofthe present invention exert an excellent effect of inhibiting productionof NO and IL-6.

Test Example 2 Anti-Inflammatory Effect 1: Effect AgainstCarrageenan-Induced Edema

[0106] (1) Test animal:

[0107] Male ICR mice (4 weeks old, Japan Charles River Co., Ltd.) werepre-bred in a breeding cage for about one week, and-healthy mice wereselected for the test.

[0108] (2) Drugs employed in the test:

[0109] Each test compound was suspended in a 0.5% carboxymethylcellulose sodium (0.5% CMC-Na solution, product of Wako Pure ChemicalIndustries, Ltd.) or dissolved in purified water. The suspension orsolution was perorally administered at a dose of 0.1 mL/10 g (bodyweight of each mouse).

[0110] λ-Carrageenan (Picnin A, product of Zushi Kagaku) dissolved inphysiological saline was used.

[0111] (3) Test method:

[0112] The volume of the right rear leg of each mouse was measured bymeans of a plethysmometer (product of Ugo Basile). Subsequently, a 2%carrageenan solution (0.05 mL) was injected into the foot pad of theleg. Five days after the injection of carrageenan (inflammation-inducingagent), the volume of the leg was measured. The mice were divided intogroups, each group containing 8 mice. From the day of division (i.e., 5days after administration of carrageenan), each test compound waspreorally administered once per day for four days. The leg volume wasmeasured before administration of each test compound and on the dayafter the final administration day (i.e., 9 days after administration ofcarrageenan). Percent edema and percent inhibition due to the testcompound were calculated in accordance with the following equations,respectively. The results are shown in Table 18.

Percent edema (%)=[(leg volume (mL) after inflammation treatment−legvolume (mL) before inflammation treatment)/(leg volume (mL) beforeinflammation treatment)]×100

Percent inhibition (%)=[percent edema of control group (%)−percent edemaof test-compound-administered group (%))/(percent edema of control group(%))]×100 TABLE 18 Amount of Percent Amount of Percent administrationinhibition administration inhibition Compounds (mg/kg) (%) Compounds(mg/kg) (%) 1A 3 30.5 1AL 10 27.6 1C 10 31.8 1AY 10 23.0 1D 10 28.6 1BJ10 38.8 1J 10 41.2 1BP 10 26.4 1K 10 42.7 1BR 10 24.9 1AT 10 20.8Indomethacin 1 23.8

[0113] The results shown in Table 18 indicate that the compounds of thepresent invention exert an excellent anti-inflammatory effect.

Test Example 3 Anti-Inflammatory Effect 2: Effect of Treating CollagenArthritis

[0114] (1) Drugs employed in the test:

[0115] Type II collagen (originating from cattle joints) was dissolvedin a 0.05M acetic acid solution, and the resultant solution was mixedwith complete Freund's adjuvant at 1:1, to thereby yield an emulsionhaving a collagen content of 1 mg/mL.

[0116] (2) Test method:

[0117] DBA/1J mice (Japan Charles River Co., Ltd.) were immunized withtype II collagen (0.1 mg/body). Twenty-one days after immunization, theanimals were boosted with same amount of type II collagen. Seven daysafter boosting, the inflammation score of the limbs of each mouse wasevaluated. The mice were divided into groups, each group containing 7mice, such that the inflammation score of the control group and that ofCompound-(1A)-administered group were virtually equal to each other.Each leg was evaluated in terms of degree of inflammation, with mostsevere conditions being rated at a score of 3 and (0: no change, 1:slight edema, 2: medium edema, 3: severe edema with joint agglutination,with a minimum unit of 0.5). The inflammation score was expressed as thesum of the scores of four limbs. The Compound (1A) of the presentinvention (0.5% CMC-Na solution) was perorally administered once per dayat a dose of 30 mg/kg/day for 23 days from the day of grouping.

[0118] The results are shown in FIG. 1. As is clear from FIG. 1, thecompounds of the present invention exert an excellent anti-inflammatoryeffect also on model chronic inflammation and are useful as drugs fortreating inflammatory diseases such as rheumatoid arthritis.

INDUSTRIAL APPLICABILITY

[0119] The imidazole derivatives (1) or salts thereof of the presentinvention exert excellent effects of inhibiting production of NO andIL-6 and are useful for preventing or treating diseases induced byoverproduction of NO and IL-6.

1. An imidazole derivative represented by formula (1):

wherein each of R¹ and R² represents a hydrogen atom, an alkyl group, ahalogen atom, an aryl group which may be substituted, or a heteroarylgroup which may be substituted; each of A, X¹, and X² represents N orCH; each of Y and Z represents O, S, SO, SO₂, CH₂, NH, or N—R⁶, whereinR⁶ represents an alkyl group, an aryl group which may be substituted, ora heteroaryl group which may be substituted; each of R³, R⁴, and R⁵represents a hydrogen atom, an alkyl group, an alkoxy group, a halogenatom, a halogenoalkyl group, a nitro group, an amino group, a hydroxylgroup, a cyano group, an acyl group, a carboxyl group, a carbamoylgroup, a substituted amide group, a sulfonamide group, a substitutedsulfonamide group, or a phenyl group which may be substituted; m is anumber of 1 to 4; and n is a number of 0 to 4, or a salt thereof.
 2. Animidazole derivative or a salt thereof as described in claim 1, whereineach of R¹ and R² represents a hydrogen atom; an alkyl group; a halogenatom; a C6-C14 aryl group which may have one to three substituentsselected from among a halogen atom, a nitro group, an amino group, analkyl group, a hydroxyl group, an alkoxy group, an alkylthio group, analkylsulfonyl group, an alkylenedioxy group, and a halogenoalkyl group;or a 5- or 6-membered heteroaryl group which has one or two atoms ofnitrogen, sulfur, or oxygen and which may have one to three substituentsselected from among a halogen atom, a nitro group, an amino group, analkyl group, a hydroxyl group, an alkoxy group, an alkylthio group, analkylsulfonyl group, an alkylenedioxy group, and a halogenoalkyl group;each of A, X¹, and X² represents N or CH; each of Y and Z represents O,S, SO, SO₂, CH₂, NH or N—R⁶, wherein R⁶ represents an alkyl group; aC6-C14 aryl group which may be substituted by an alkyl group, an alkoxygroup, an amino group, or a sulfonamide group; or a 5- or 6-memberedheteroaryl group which has one or two atoms of nitrogen, sulfur, oroxygen and which may be substituted by an alkyl group, an alkoxy group,an amino group, or a sulfonamide group; each of R³, R⁴, and R⁵represents a hydrogen atom, an alkyl group, an alkoxy group, a halogenatom, a halogenoalkyl group, a nitro group, an amino group, a hydroxylgroup, a cyano group, an alkanoyl group, a carboxyl group, a carbamoylgroup, an alkanoylamino group, a sulfonamido group, an alkanesulfonamidogroup, or a phenyl group which may be substituted by an alkyl group, analkoxy group, an-amino group, or a sulfonamido group; m is a number of 1to 4; and n is a number of 0 to
 4. 3. A drug comprising, as an activeingredient, an imidazole derivative or a salt thereof as recited inclaim 1 or
 2. 4. A drug as described in claim 3, which is a drug forpreventing or treating a disease induced by overproduction of nitricoxide or IL-6.
 5. A drug composition comprising an imidazole derivativeor a salt thereof as recited in claim 1 or 2 and a pharmaceuticallyacceptable carrier.
 6. Use of an imidazole derivative or a salt thereofas recited in claim 1 or 2 for producing a drug.
 7. Use as described inclaim 6, wherein the drug is a drug for preventing or treating a diseaseinduced by overproduction of nitric oxide or IL-6.
 8. A method fortreating a disease induced by overproduction of nitric oxide or IL-6characterized by comprising administrating an imidazole derivative or asalt thereof as recited in claim 1 or 2.